The mission of the Pharmacology & Experimental Therapeutics Section (PETS) of NCI's Pediatric Oncology Branch (POB) is to develop more effective treatments for children and young adults with refractory cancers and genetic tumor predisposition syndromes (GTPS). Promising novel agents are studied in early clinical trials that evaluate toxicities, activity, pharmacokinetics, and pharmacodynamics. By leveraging unique NIH resources, I have applied the principles of drug development for refractory cancers to neurofibromatosis type 1 (NF1)-related tumors and built the nation's largest comprehensive NF1 clinical trials program directed at plexiform neurofibromas (PN) and malignant peripheral nerve sheath tumors (MPNST). My team was able to comprehensively characterize the natural history of PN and other NF1 manifestations, knowledge which is required for approval of novel agents for PN. I recently identified the first active agent (partial response rate more than 50%) for large, symptomatic PN using the MEK inhibitor Selumetinib. In collaboration with CTEP and AstraZeneca, I developed a multi-site phase II registration study, which is expected to complete enrollment in June 2016. This effort has been expanded to hereditary medullary thyroid carcinoma (MTC) in children and young adults with multiple endocrine neoplasia (MEN) 2B, and other GTPS and rare tumors. Due to distinct characteristics of GTPS, the Section has developed new trial designs, methods of image analysis, and trial endpoints, which allow for more meaningful and safe evaluation of novel agents. For example, our method of automated volumetric MRI analysis of NF1 PN is used in most clinical trials nationwide to centrally (at the NCI) perform response evaluation as primary endpoints The Section uses a highly collaborative approach to accomplish research goals. For the translation of promising preclinical discoveries into clinical trials for refractory cancers, I built a strong collaboration with Dr. Lee Helman, who is leading the NIH wild-type gastrointestinal stromal tumor (wt-GIST) clinic. Collaboration with the Division of Cancer Treatment and Diagnosis (DCTD) medical oncology team led by Dr. Alice Chen has allowed us to simultaneously enroll pediatric and adult patients, when scientifically meaningful, for example in clinical trials directed at rare sarcomas. For the development of clinical trials for NF1 related tumors, I have extensive and longstanding collaborations with basic extramural investigators, who perform preclinical trials in relevant mouse models of NF1, including Dr. Karen Cichowski (Brigham and Women's Hospital) for MPNST, Dr. Nancy Ratner (Cincinnati Children's Hospital) and Dr. Wade Clapp (Indiana University) for PN, and with the NF Preclinical Trials Consortium. Dr. Karlyne Reilly, a basic scientist with great expertise in NF1 mouse models and a founding member of the NCI Rare Tumor Initiative (RTI), recently joined the efforts of the Section to guide preclinical studies to advance therapies for PN and MPNST. PETS clinical trials are conducted as single- and limited-institution studies, as well as multi-center studies or with cooperative groups [Children's Oncology Group (COG) Phase I/Pilot Consortium, Sarcoma Alliance for Research through Collaboration (SARC), NF Clinical Trials Consortium]. Several of our studies include genomic analyses, for which we have established collaborations with Dr. Paul Meltzer (NCI CCR), Dr. Javed Khan (NCI CCR), and Dr. Douglas Stewart (NCI DCEG). I am working closely with the NCI Cancer Therapy Evaluation Program (CTEP) and the pharmaceutical industry, and have successfully competed for funding to support preclinical collaborations and extramural investigators on clinical trials through Department of Defense (DoD) Clinical Trial Awards (CTA), NIH Bench to Bedside awards, Children's Tumor Foundation (CTF) awards, and U01 grants. I am also a Clinical Science Co-Leader on a SPORE project directed by Drs. Wade Clapp and Kevin Shannon: Developmental and HyperActive Ras Tumor (DHART) SPORE. My section also provides support to POB, CCR, and NIH investigators for the design of preclinical, clinical, and pharmacokinetic (PK) studies, drug assay development, and analysis of PK data. Central nervous system (CNS) pharmacology of anticancer drugs is studied in collaboration with Dr. Kathy Warren, Head of the Pediatric Neuro-Oncology Section (PNOS), in her non-human primate model.